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Transcranial magnetic stimulation (TMS) is a powerful non-invasive technique for the modulation of brain activity. While the precise mechanism of action is still unknown, TMS is applied in cognitive neuroscience to establish causal relationships between stimulation and subsequent changes in cerebral function and behavioral outcome. In addition, TMS is an FDA-approved therapeutic agent in psychiatric disorders, especially major depression. Successful repetitive TMS in such disorders is usually applied over the left dorso-lateral prefrontal cortex (DLPFC) and treatment response mechanism was therefore supposed to be based on modulations in functional networks, particularly the meso-cortico-limbic reward circuit. However, mechanistic evidence for the direct effects of rTMS over DLPFC is sparse. Here we show the specificity and temporal evolution of rTMS effects by comparing connectivity changes within 20 common independent components in a sham-controlled study. Using an unbiased whole-brain resting-state network (RSN) approach, we successfully demonstrate that stimulation of left DLPFC modulates anterior cingulate cortex (ACC) connectivity in one specific meso-cortico-limbic network, while all other networks are neither influenced by rTMS nor by sham treatment. The results of this study show that the neural correlates of TMS treatment response are also traceable in DLPFC stimulation of healthy brains and therefore represent direct effects of the stimulation procedure. [ABSTRACT FROM AUTHOR]

• Interleaved TMS/fMRI setup reveals direct effects of DLPFC stimulation. • Acute activation changes during TMS/fMRI co-localize with resting-state network that is modulated after rTMS. • Discovered network component might be a future marker for MDD treatment success. Transcranial magnetic stimulation (TMS) is an FDA-approved therapeutic option for treatment resistant depression. However, exact mechanisms-of-action are not fully understood and individual responses are variable. Moreover, although previously suggested, the exact network effects underlying TMS' efficacy are poorly understood as of today. Although, it is supposed that DLPFC stimulation indirectly modulates the sgACC, recent evidence is sparse. Here, we used concurrent interleaved TMS/fMRI and state-of-the-science purpose-designed MRI head coils to delineate networks and downstream regions activated by DLPFC-TMS. We show that regions of increased acute BOLD signal activation during TMS resemble a resting-state brain network previously shown to be modulated by offline TMS. There was a topographical overlap in wide spread cortical and sub-cortical areas within this specific RSN#17 derived from the 1000 functional connectomes project. These data imply a causal relation between DLPFC-TMS and activation of the ACC and a broader network that has been implicated in MDD. In the broader context of our recent work, these data imply a direct relation between initial changes in BOLD activity mediated by connectivity to the DLPFC target site, and later consolidation of connectivity between these regions. These insights advance our understanding of the mechanistic targets of DLPFC-TMS and may provide novel opportunities to characterize and optimize TMS therapy in other neurological and psychiatric disorders. [ABSTRACT FROM AUTHOR]